This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objectives of this project are to evaluate the roles of DNA double strand break repair in normal hematopoietic cells and microenvironments, and to assess whether specific cell types in the bone marrow niche relate to tumorigenesis. Nonhomologous end joining (NHEJ), a critical DSB repair pathway, is an important suppressor of oncogenic genome instability in developing lymphocytes. New reports now also point to a role for DSB repair in maintaining stem cell function over time, and we have recently shown that NHEJ is an important suppressor of tumorigenesis in non-lymphoid tissues. Using mice deficient for the NHEJ factor ARTEMIS and for the tumor suppressor p53, we will test our hypotheses: 1) that the NHEJ pathway is critical for the fitness and function of normal hematopoietic cells, and 2) that bone marrow and lymphoid microenvironments are key determinants of pre-B cell leukemogenesis and lymphomagenesis. Aim 1. To evaluate the extent to which NHEJ is required for normal function or homeostasis of cells in the hematopoietic compartment, we will: 1.1. measure HSC-derived cell populations in bone marrow and in circulation, and test whether NHEJ-deficient HSCs show defects in differentiation or fitness 1.2. assess genome instability in NHEJ-deficient stem and progenitor cell populations Aim 2. To determine whether specific stem cell or lymphoid microenvironments participate in shaping lymphoma phenotype, we will: 2.1. determine whether tumor latency, homing potential, or molecular etiology is differentially influenced by lympho-competent versus lympho-deficient bone marrow microenvironments 2.2. test whether tumor cells become adapted to specific secondary lymphoid microenvironments